Drug Interactions Speaker Has No Relationship to Disclose

8/11/17

Things that go BOOM! Common Dangerous Drug Interactions Speaker has no relationship to disclose.

Amelie Hollier, DNP, FNP-BC, FAANP President, CEO APEA Lafayette, LA

St. John’s Wort Hypericum perforatum CYP 3A4 Enzymes • Antidepressant, antianxiety • CYP450 enzyme system properties • 3A4 metabolizes about 50% of all • 3A4 inducer (causes certain drugs clinically useful medications to be metabolized more rapidly) • Most abundant and clinically significant • Actually composed of 4 enzymes: 3A3, 3A4, 3A5, 3A7 3A4 Borrelli F, Izzo AA. Herb-drug interactions with St John's wort (Hypericum perforatum): an update on clinical observations. AAPS J. 2009;11:710-727.

When a substance Clinical Example 1: is an “Inducer” St. John’s wort - Inducer Patient is on indinavir (Crixivan). He begins to •Speeds up take St. John’s wort for depression. metabolism Potential problem: Increased viral load. •Decreases affect of drugs (usually) Reason: St. John’s wort is 3A4 inducer and causes reduced efficacy of indinavir due to rapid metabolism.

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Clinical Example 2: St. John’s Wort St. John’s wort - Inducer Hypericum perforatum Patient had a kidney transplant and • Hyperforin is bioactive takes cyclosporine. He starts taking component of St. John’s wort St. John’s wort for depression. • Hyperforin probably responsible for antidepressant/antianxiety Potential problem: Transplant rejection. properties AND INDUCTION of Reason: St. John’s wort is 3A4 inducer and 3A4/3A5 enzymes causes rapid metabolism of cyclosporine.

Antirejection properties are diminished. Borrelli F, Izzo AA. Herb-drug interactions with St John's wort (Hypericum perforatum): an update on clinical observations. AAPS J. 2009;11:710-727.

2. SSRIs/SNRIs TCAs, “Other” Serotonin, Serotonin, and more Serotonin Serotonin, Serotonin, and more Serotonin SSRIs SNRIs Tricyclic Antidepressants “Other” (Serotonin-Reuptake (Serotonin-Norepinephrine Inhibitors) Reuptake Inhibitors) Amitriptyline (Elavil) Trazodone (Oleptro) Escitalopram (Lexapro) Duloxetine (Cymbalta) Desipramine (Norpramin) Mirtazapine (Remeron) Citalopram (Celexa) Venlafaxine (Effexor) Doxepin Vilazodone (Viibryd) Fluoxetine (Prozac) Levo milnacipran (Fetzima) Nortriptyline (Pamelor) Nefazodone (Serzone) Fluvoxamine (Luvox) Desvenlafaxine (Pristiq) Anafranil (Clomipramine) Vortioxetine (Trintellix) Paroxetine (Paxil) Venlafaxine (Effexor) Imipramine (Tofranil) Sertraline (Zoloft) Protriptyline (Vivactil)

Quiz What common Serotonin Syndrome medication used to •Occurs when central and treat depressive peripheral 5HT-1A and 5HT-2A disorder, ADHD, receptors are overstimulated and seasonal affective disorder hasn’t been mentioned?

Why NOT? Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. Ochsner J. 2013;13:533-540.

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Serotonin Syndrome Manifestations of Why does this occur? Serotonin Syndrome 2 or more serotonergic drugs • Autonomic changes: diarrhea, fever, interact with each other flushing, hypo/hypertension, sweating • Neuromuscular changes: hyperreflexia, increased muscle tone, restlessness, rigidity, tremor, shivering • Central Nervous system: Agitation, confusion, delirium, hallucinations

Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. Ochsner J. 2013;13:533-540. Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. Ochsner J. 2013;13:533-540.

What Medication Combos? SSRI/SNRI plus: By What Mechanism? • Tryptophan (OTC) • Increased serotonin production: Tryptophan • Inhibition of serotonin reuptake: DM, TCAs, • Dextromethorphan (DM), codeine, St. John’s wort, tramadol TCAs, St. John’s wort, tramadol • Inhibition of serotonin metabolism: • Linezolid Linezolid • Meperidine, ecstasy, mirtazapine • Increased serotonin release: DM, meperidine, ecstasy, mirtazapine • Buspirone, LSD, metoclopramide, • Stimulation of serotonin receptors: triptans Buspirone, LSD, metoclopramide, triptans

Serotonin Syndrome Quiz: •Usually within 6 hours of Patient takes ingestion of the offending sertraline (or your substance fave SSRI) daily for depression. She has migraine headaches. May a triptan be safely prescribed for her?

Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin syndrome. Ochsner J. 2013;13:533-540.

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What about SSRIs/SNRIs Quiz: plus Triptans? A 42 year old male patient has had 3 back surgeries and has chronic low back pain. • Weigh risk/benefit but He takes 60 mg duloxetine daily, 50 mg evidence does not amitriptyline HS, gabapentin 300 mg TID support avoidance of and tramadol 100 mg (with 650 mg triptans (if this is the acetaminophen) 1-3 times daily PRN pain. only serotonergic med When he is unable to sleep, he takes she takes) trazodone 25 mg HS. He has zolpidem • Monitor! (Ambien) 5 mg for sleep if trazodone doesn’t help. vans RW, Tepper SJ, Shapiro RE, Sun-Edelstein C, Tietjen GE. The FDA alert on serotonin syndrome with What’s a likely potential problem? use of triptans combined with selective serotonin reuptake inhibitors or selective serotonin- norepinephrine reuptake inhibitors: American Headache Society position paper. Headache. 2010;50:1089-1099.

How could you manage this to Medication Assessment decrease likelihood of Medication Effect on Serotonin serotonin syndrome? Gabapentin None Prescriber Strategy 1: Decrease serotonin load! Acetaminophen None Can we decrease or stop a med? Which one? Zolpidem None Medication Effect on Serotonin Amitriptyline 50 mg HS Inhibit serotonin reuptake Gabapentin None Trazodone 25 mg HS Inhibit serotonin reuptake Acetaminophen None Zolpidem None Tramadol 100 mg-300 mg Inhibit serotonin reuptake Amitriptyline 50 mg HS Inhibit serotonin reuptake Duloxetine 60 mg daily Inhibit serotonin reuptake Trazodone 25 mg HS Inhibit serotonin reuptake Tramadol 100 mg-300 mg Inhibit serotonin reuptake If he’s not having problems now, he is very likely to have one soon! Duloxetine 60 mg daily Inhibit serotonin reuptake

How could you manage this to decrease likelihood of serotonin syndrome? Medication Assessment

Strategy 2: Patient education! Medication Effect on Serotonin No OTCs without checking with pharmacist! Gabapentin None Do not exceed dose of ANY medication!!!!! Acetaminophen None Medication Effect on Serotonin Zolpidem None Gabapentin None Amitriptyline 50 mg HS Inhibit serotonin reuptake Acetaminophen None Trazodone 25 mg HS Inhibit serotonin reuptake Zolpidem None Tramadol 100 mg-300 mg Inhibit serotonin reuptake Amitriptyline 50 mg HS Inhibit serotonin reuptake Duloxetine 60 mg daily Inhibit serotonin reuptake Trazodone 25 mg HS Inhibit serotonin reuptake Suppose he develops a cough and asks about Tramadol 100 mg-300 mg Inhibit serotonin reuptake Robitussin DM (dextromethorphan)? Duloxetine 60 mg daily Inhibit serotonin reuptake What med could he safely receive for cough?

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Take Home Point! What Medication Combos? SSRI/SNRI plus: Serotonin Syndrome is real and • Tryptophan (OTC) there’s no test to identify it. • Dextromethorphan (DM), codeine, Must have an index of suspicion! TCAs, St. John’s wort, tramadol • Linezolid • Meperidine, ecstasy, mirtazapine • Buspirone, LSD, metoclopramide, triptans

Statins Statins plus Gemfibrozil • Most drug drug interactions (DDIs) • Gemfibrozil used to treat mixed related to CYP450 (except pravastatin) dyslipidemia and • CYP3A4 and CYP2C9 enzymes hypertriglyceridemia, type IV, V involved • Most interactions occur with simvastatin and lovastatin

Wiggins BS, Saseen JJ, Lee R, et al. Recommendations for management of clinically significant drug-drug interactions with statins and selective agents used in patients with cardiovascular disease: a scientific statement from the American Heart Association. Circulation. Published online October 17, 2016. http://circ.ahajournals.org/content/early/2016/10/17/CIR.0000000000000456. Accessed February 25, 2017.

Statins plus Gemfibrozil Statins plus Gemfibrozil Muscle TOXICITY!!! • Increases concentration of statins; Do not use in combo!!! • Muscle TOXICITY!!! • Rosuvastatin concentration increased 56% - 88% • Pravastatin increased > 100%

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Quiz: Best Answer: Fenofibrate Patient takes pravastatin (LDL elevation) and has FYI: If gemfibrozil MUST be triglyceride levels >500. used, the authors preferred What fibrate may be safely atorvastatin, pitavastatin, prescribed for her elevated rosuvastatin, or fluvastatin. triglycerides?

Quiz: Any worries about prescribing amlodipine plus: What about Calcium Channel Simvastatin? Lovastatin? Blockers and Rosuvastatin? Statins? Pravastatin? Pitavastatin? Atorvastatin?

Quiz: What’s the problem with Calcium Channel Blockers prescribing amlodipine plus: Decrease BP Decrease HR Simvastatin? Long DHPs Non-DHPs Lovastatin? • Norvasc (amlodipine) • Cardizem, Tiazac • Procardia (Diltiazem) (nifedipine) • Calan, Covera • Plendil (felodipine) HS, Verelan (verapamil) • Dynacirc (isradipine) • Cardene (nicardipine) Don’t exceed 20 mg of Simva/Lova if concomitant amlodipine. Wiggins BS, Saseen JJ, Lee R, et al. Recommendations for management of clinically significant drug-drug interactions with statins and selective agents used in patients with cardiovascular disease: a scientific statement from the American Heart Association. Circulation. Published online October 17, 2016. Non-DHPs decrease Heart Rate (and BP a little) http://circ.ahajournals.org/content/early/2016/10/17/CIR.0000000000000456. Accessed February 25, 2017.

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Quiz: Any worries about Quiz: Any worries about prescribing diltiazem plus: prescribing diltiazem plus:

Simvastatin? Simvastatin? (don’t exceed 10 mg) Lovastatin? Lovastatin? (don’t exceed 20 mg) Atorvastatin? AHA: Avoid Simva/Lova with diltiazem or verapamil

Atorvastatin? (minor increase) AHA: Monitor Wiggins BS, Saseen JJ, Lee R, et al. Recommendations for management of clinically significant drug-drug interactions with statins and selective agents used in patients with cardiovascular disease: a scientific statement from the American Heart Association. Circulation. Published online October 17, 2016. http://circ.ahajournals.org/content/early/2016/10/17/CIR.0000000000000456. Accessed February 25, 2017.

Digoxin plus Statins? More Problems: Other Medications plus Statins? Not usually any worries about • Amiodarone (Cordarone) increased digoxin levels. • Dronedarone (Multaq) Exception: High doses of atorvastatin • Warfarin (any statin-check INR after starting) • Ticagrelor (Brilinta) • Immunosuppressants • Colchicine

Wiggins BS, Saseen JJ, Lee R, et al. Recommendations for management of clinically significant drug-drug interactions with statins and selective agents used Wiggins BS, Saseen JJ, Lee R, et al. Recommendations for management of clinically significant drug-drug interactions with statins and selective agents used in patients with cardiovascular disease: a scientific statement from the American Heart Association. Circulation. Published online October 17, 2016. in patients with cardiovascular disease: a scientific statement from the American Heart Association. Circulation. Published online October 17, 2016. http://circ.ahajournals.org/content/early/2016/10/17/CIR.0000000000000456. Accessed February 25, 2017. http://circ.ahajournals.org/content/early/2016/10/17/CIR.0000000000000456. Accessed February 25, 2017.

Take Home Point: TMP/SMX • Many medication issues Drug Interactions • You’ll see this as a New Drug Interaction with statins in your Smart Phone Apps! • Too many to remember • Possible HYPERKALEMIA when TMP- SMX combined with meds that increase • Check for drug interactions potassium • ACEs, ARBs, potassium sparing diuretics, NSAIDs

Prescribers Letter; January 2015; Vol 31 Paauw DS. Hyperkalemia: the riskiest drugs. Medscape Internal Medicine. September 3, 2015. http://www.medscape.com/viewarticle/850360 Accessed February 25, 2017.

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TMP/SMX TMP/SMX Drug Interactions Drug Interactions • Trimethoprim decreases excretion of • 81.5% had significant increase in serum potassium (acts on the distal nephron, K from baseline blocking the epithelium Na channel • 18% had hyperkalemia > 5 meq/L which leads to reduction in renal excretion of K) • 6% had hyperkalemia > 5.5 meq/L • Hyperkalemia develops 4-5 days after • Reversible once TMP/SMX is d/c’d taking TMP/SMX, so 3 day dose likely OK Prescribers Letter; January 2015; Vol 31 Paauw DS. Hyperkalemia: the riskiest drugs. Medscape Internal Medicine. September 3, Alappan R, Buller GK, Perazella MA. Trimethoprim-sulfamethoxazole therapy in 2015. http://www.medscape.com/viewarticle/850360 Accessed February 25, 2017. outpatients: is hyperkalemia a significant problem? Am J Nephrol 1999;19:389-94.

Drug Interactions Care in These Patients! • 6% of patients on TMP/SMX develop • Elderly hyperkalemia (>5.5 meq/L) • Renal insufficiency • Hospitalizations increase 7-fold when elders take TMP-SMX with ACE, ARB, • DM etc • Heart failure • Even higher when combined in patients who take ACEs, ARBs, or ***If no alternative to TMP/SMX, check K level spironolactone after day 3

Prescribers Letter; January 2015; Vol 31 Prescribers Letter; January 2015; Vol 31 Paauw DS. Hyperkalemia: the riskiest drugs. Medscape Internal Medicine. September 3, Paauw DS. Hyperkalemia: the riskiest drugs. Medscape Internal Medicine. September 3, 2015. http://www.medscape.com/viewarticle/850360 Accessed February 25, 2017. 2015. http://www.medscape.com/viewarticle/850360 Accessed February 25, 2017.

TOP 20 Dispensed Rx’s Synthroid (levothyroxine) Medication Medication 1. Levothyroxine 11. Amoxicillin • 2-5/100 patients has 2. Acetaminophen/hydrocodone 12. Fluticasone hypothyroidism 3. Lisinopril 13. Gabapentin 4. Metoprolol 14. Alprazolam • Thyroid supplement for patients 5. Atorvastatin 15. Hydrochlorothiazide with hypothyroidism (T4) 6. Amlodipine 16. Azithromycin • Enhance oxygen consumption by 7. Metformin 17. Furosemide most tissues in the body and 8. Omeprazole 18. Sertraline increase metabolic rate and 9. Simvastatin 19. Tramadol metabolism of carbs, protein, and 10. Albuterol 20. Losartan lipids

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Synthroid (levothyroxine) What else effects

•T4 absorbed in the small bowel absorption of when taken orally levothyroxine besides •Absorption varies from 40- food? 80% •Prefer daily oral dose, empty stomach, 30 minutes before food is eaten •Fasting increases absorption of T4

5. PPIs plus PPIs levothyroxine • Dexlansoprazole (Dexilant) • Esomeprazole (Nexium) • Lansoprazole (Prevacid) • Omeprazole (Prilosec) • Pantoprazole (Protonix) • Rabeprazole (Aciphex)

Quiz: Patient who has Levothyroxine plus hypothyroidism takes levothyroxine (TSH = 2.5). PPIs She starts an OTC PPI. What is • More levothyroxine may be likely to happen to her TSH? needed when patients are on acid suppressing medications 1. It will increase • A median increase in TSH of .12 2. It will decrease mU/L 3. It will stay the same • Levothyroxine better absorbed in 4. I don’t have a clue an acidic environment Irving SA, Vadiveloo T, Leese GP. Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS). Clin Endocrinol (Oxf). 2015;82:136-141. Bolk N, Visser TJ, Nijman J, et al. Effects of evening vs morning levothyroxine intake: a randomized double-blind crossover trial. Arch Intern Med 2010;170:1996-2003.

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Effects of Food/Meds Levothyroxine: Decreased Interacting Substance Comments Absorption with Other Meds H2 blockers, PPIs Median increase in TSH of 0.12 • Aluminum hydroxide mU/L • Bile acid sequestrants Calcium Salts Decreases absorption about 20%; median TSH increase 0.27 mU/L • Iron salts Coffee, espresso Reduces absorption about one- • Estrogen third (wait an hour but at least 30 mins) • Magnesium salts Iron salts Median increase in TSH 0.22 mU/L • Orlistat (Xenical) • Simethicone Statins Median decrease in TSH 0.17 mU/L; mechanism unknown • Soy

Prescribers letter 2015; 22(4):310420 • Sucralfate (Carafate) Jonklass J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism. Thyroid Irving SA, Vadiveloo T, Leese GP. Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS). Clin Endocrinol (Oxf). 2015;82:136-141. 2014;24:1670-751. Irving SA, Vadiveloo T, Leese GP. Drugs that interact with levothyroxine: an observational study from Bolk N, Visser TJ, Nijman J, et al. Effects of evening vs morning levothyroxine intake: a randomized double-blind the Thyroid Epidemiology, Audit and Research Study (TEARS). Clin Endocrinol 2015;82:136-41. crossover trial. Arch Intern Med 2010;170:1996-2003.

Take Home Point Proton Pump Inhibitors

•If euthyroid patient • 2-3 fold increase in risk of acute starts/stops acid suppression kidney injury (AKI) in elderly therapy, check TSH in 4-8 patients weeks •Remind patient to let you know if taking OTC meds

Antoniou T, Macdonald EM, Hollands S, et al. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJO. 2015;3:e166-e171.

PPI Use Associated 6. NSAIDs with: • Increased risk of acute kidney injury • Incident chronic kidney disease • CKD progression • End-stage renal disease (ESRD) DOI: http://dx.doi.org/10.1016/j.kint.2016.12.021

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Triple Whammy= risk Triple Whammy of acute kidney injury • ACE/ARB: reduce glomerular filtration pressure via vasodilation of the efferent arteriole ACE or ARB plus diuretic • NSAID/ASA: inhibits renal prostaglandin synthesis (inhibits dilation of renal arteries plus NSAID and decreases blood flow to the glomerulus) • Diuretics decrease intravascular volume and reduce blood flow to the glomerulus The combo leads to reduction in renal blood flow and renal dysfunction Dreischulte T, Morales DR, Bell S, Guthrie B. Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury. Kidney Int. 2015 Apr 15.

Community Acquired- Community Acquired- Acute Kidney Injury (AKI) Acute Kidney Injury (AKI) • Study: 78,000 patients • AKI defined as 1.5 fold or more above baseline When NSAID added: • RAS or diuretic increased risk, no NSAIDs • 66% increased risk of AKI • RAS plus diuretic 2x risk, no NSAIDs • Highest risk: NSAID, ACE/ARB, loop • Greatest risk: loop diuretic, RAS inhibitor, diuretic, and aldosterone antagonists and aldosterone antagonist diuretic, no • When AKI developed: 10x risk of NSAIDs hospitalization, 4-5x risk of death • Risk highest in patients > 75 y/o or existing kidney disease Dreischulte T, Morales DR, Bell S, Guthrie B. Combined use of nonsteroidal anti-inflammatory drugs with diuretics Dreischulte T, Morales DR, Bell S, Guthrie B. Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury. Kidney Int. and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury. Kidney Int. 2015 Apr 15. 2015 Apr 15.

Triple Whammy Protection from the Triple Whammy •Especially deleterious in •Keep well hydrated elderly patients, diabetics, renal insufficiency, ascites, •NSAID use: 6-12 hour (not or HF (“double whammy” 24 hours) can cause acute injury) •Avoid NSAID, use tramadol, acetaminophen instead, other modality Dreischulte T, Morales DR, Bell S, Guthrie B. Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury. Kidney Int. 2015 Apr 15.

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Teaching Point 6. Warfarin and Antimicrobials • Stop diuretic (and NSAID) if at risk for volume depletion (diarrhea, vomiting, unable to drink, etc.)

Quiz: Patient takes warfarin TMP/SMX therapy. Stable INR. •Raise INR and increase She develops a UTI and is given bleeding risk 2-4 fold; TMP/SMX. especially in older patients What is likely to happen to her •Consider alternative INR?

1. It will increase 2. It will decrease 3. It will stay the same 4. I don’t have a clue

Mechanism of Action Quiz: 60 y/o female takes warfarin with TMP/SMX therapy. Stable INR. She develops a UTI • Displacement of warfarin What is prudent antibiotic to treat from protein binding sites her UTI? • Alterations in gut flora 1. 3 days of ciprofloxacin • Increased INR seen with 3 2. 7 days of ciprofloxacin day course of TMP/SMX 3. Nitrofurantoin 5 days 4. 3 days of TMP/SMX

Bungard TJ, Yakiwchuk E, Foisy M, Brocklebank C. Drug interactions involving warfarin: Bungard TJ, Yakiwchuk E, Foisy M, Brocklebank C. Drug interactions involving warfarin: practice tool and practical management tips. CPJ/RPC 2011;144:21-34. practice tool and practical management tips. CPJ/RPC 2011;144:21-34.

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Quiz: 70 y/o male takes warfarin therapy. Stable INR. What do we know? He has diarrhea secondary to C. • Metronidazole will raise INR difficile. and increase bleeding risk 2-4 Is metronidazole a good choice to fold; especially in older patients treat his C. diff? • Consider alternative

Bungard TJ, Yakiwchuk E, Foisy M, Brocklebank C. Drug interactions involving warfarin: practice tool and practical management tips. CPJ/RPC 2011;144:21-34.

Mechanism of Action: TMP/SMX or Metronidazole Oral Metronidazole •IF no alternative: consider • Inhibits metabolism of warfarin empirically lowering the • Topical preparations associated warfarin dose 25%-40% if at with less systemic absorption high risk of bleed so, less likely to increase INR

Bungard TJ, Yakiwchuk E, Foisy M, Brocklebank C. Drug interactions involving warfarin: Bungard TJ, Yakiwchuk E, Foisy M, Brocklebank C. Drug interactions involving practice tool and practical management tips. CPJ/RPC 2011;144:21-34. warfarin: practice tool and practical management tips. CPJ/RPC 2011;144:21-34.

Take Home Point Rifampin • Can decrease INR Generally speaking • May take several weeks to • Monitor INR about 5 days see full effect after starting drug, then when •Check INR for several weeks drug is stopped after starting rifampin •EXCEPTION: Rifampin • Consider increasing warfarin dose by 25%-50%

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Take Home Point 6. Warfarin and Acetaminophen • Oral cephalosporins (cefaclor, cefixime, cefpodoxime, cefuroxime) not been shown to interact with warfarin • Oral penicillin G, ampicillin probably do not interact

Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005;165:1095-106.

Take Home Point Mechanism of Action •Regular use of Acetaminophen acetaminophen will increase • Hepatic metabolism of INR warfarin is inhibited • Check INR after 3-5 days of acetaminophen use • Not necessary for occasional use

Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and Bungard TJ, Yakiwchuk E, Foisy M, Brocklebank C. Drug interactions involving warfarin: food interactions. Arch Intern Med 2005;165:1095-106. practice tool and practical management tips. CPJ/RPC 2011;144:21-34.

7. Grapefruit and the CYP 3A4 3A4 substrates Substrates • A medication that requires 3A4 enzymes to metabolize it is known as a 3A4 substrate

3A4

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CYP 3A4 Enzymes CYP 3A4 Inhibitor •These liver enzymes •Medication or substance that metabolize 3A4 substrates prevents the 3A4 enzymes from metabolizing 3A4 substrates

3A4 3A4

Don’t mix substrates and Inhibitors! 3A4 Substrate 3A4 Inhibitors Ondansetron (Zofran) Clarithromycin (Strong) Take Home Point: Clarithromycin, erythromycin Ketoconazole (Strong) Dextromethorphan Many protease inhibitors Combining (Strong) Substrates with Most calcium channel blockers Erythromycin (Intermediate) Atorvastatin, lovastatin, Grapefruit juice (Intermediate) their Inhibitors is simvastatin Cyclosporin Verapamil, diltiazem NEVER a good (Intermediate) Many benzos Cimetidine (Weak) idea!!! Salmeterol Ciprofloxacin (Possible) Cocaine Mayomedicallaboratories.com; Curr Drug Metab. 2008 May;9(4):310-22; www.fda.gov

Take Home Point: The 7 Sins! • Too many to remember • Always check for drug 1. St. John’s Wort interactions 2. SSRIs, SNRIs 3. Statins 4. ACEs/ARBs 5. PPIs 6. Warfarin 7. TMP/SMX

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Top 10 CYP450 Drugs Top 10 Drugs to watch out for! to watch out for! 5. Bactrim 10. Ciprofloxacin 4. Paroxetine & Fluoxetine 9. Cimetidine 3. Phenytoin 8. Warfarin 2. Levothyroxine 7. Erythro/clarithro 1. Atorvastatin/Simvastatin 6. Ketoconazole

Thank you! To contact me or for questions: 2D6 [email protected]

Amelie Hollier, DNP, FNP-BC, FAANP 3A4